The naturally attenuated Kunjin strain of West Nile virus shows enhanced sensitivity to the host type I interferon response

The host determinants that contribute to attenuation of the naturally occurring nonpathogenic strain of West Nile virus (WNV), the Kunjin strain (WNV KUN ), remain unknown. Here, we show that compared to a highly pathogenic North American strain, WNV KUN exhibited an enhanced sensitivity to the antiviral effects of type I interferon. Our studies establish that the virulence of WNV KUN can be restored in cells and mice deficient in specific interferon regulatory factors (IRFs) or the common type I interferon receptor. Thus, WNV KUN is attenuated primarily through its enhanced restriction by type I interferon- and IRF-3-dependent mechanisms.